This Phase I STTR project seeks to demonstrate proof of principle that novel, targetable nanoparticles can delivery therapeutic substances to human tumor cells and reduce tumor burden in metastatic cancer. The concept for these nanoparticles is based on the polymerized liposome nanoparticle (PLN) that displays functional antibodies that target tumor cell surface markers. The therapeutic cargos are encapsulated cytotoxic drugs that comprise the front line treatment for Ewing sarcoma. Upon recognition by the tumor cell, the nanoparticle binds, gets taken into the cell (endocytosed) and the nanoparticle cargo is released, ultimately allowing availability of the drug to kill the cancer cel. This project fits well within the mission of the NCI, to develop new nanotechnology-based therapeutics. Treatment-resistant metastases are the ultimate cause of death in most cancer patients. Systemic therapy for metastases is generally ineffective. A reliable, low-toxic, highly effective therapy is urgently needed to treat both relapse patients and treatment- resistant metastases. The specific aims of this proposal are therefore to carry out efficient encapsulation of cancer drugs inside targeted PLNs and demonstrate efficacy in killing cancer cells in a xenograft mouse model of metastatic human Ewing sarcoma. NanoValent's goal, at the conclusion of the STTR Phase II is to assemble the necessary data for an IND submission to the FDA for approval of this novel therapy, initially for use in relapsed Ewing sarcoma patients.